ADENOVIRUS E1A PROTEINS INHIBIT ACTIVATION OF TRANSCRIPTION BY P53

p53 stimulates the transcription of a number of genes, such as MDM2, W af1, and GADD45. We and others have shown previously that this activit y of p53 can be inhibited by adenovirus type 2 or 12 large E1B protein s, Here we show that the adenovirus E1A proteins also can repress the stimulation of transcription by p53, both in transient transfections a nd in stably transfected cell lines, The inhibition by E1A occurs with out a significant effect on the DNA-binding capacity of p53. Furthermo re, the activity of a fusion protein containing the N-terminal part of p53 linked to the GAL4 DNA-binding domain can be suppressed by E1A, T his indicates that E1A affects the transcription activation domain of p53, although tryptic phosphopeptide mapping revealed that the level o f phosphorylation of this domain does not change significantly in E1A- expressing cell lines, Gel filtration studies, however, showed p53 to be present in complexes of increased molecular weight as a result of E 1A expression, Apparently, E1A can cause increased homo- or hetero-oli gomerization of p53, which might result in the inactivation of the tra nscription activation domain of p53, Additionally, we found that trans fectants stably expressing E1A have lost the ability to arrest in G(1) after DNA damage, indicating that E1A can abolish the normal biologic al function of p53.